Program Director/Principal Investigator: Amel, Karaa PROJECT SUMMARY Primary mitochondrial diseases (PMD) are a group of genetically and phenotypically heterogeneous inherited metabolic disorders with a combined prevalence of 1 in 5000 people. The frequency is likely higher due to under-recognized and undiagnosed cases even as we continue to discover new genes. Despite hundreds of mitochondrial (mtDNA) and nuclear DNA (nDNA) defects found to be responsible for PMD, many more remain to be uncovered. Patients with clinical and biochemical features highly suspected of PMD remain without a specific molecular diagnosis despite ever expanding genetic panels and methodologies for genetic testing. With increased interest in mitochondrial biology in health and disease and the conduct of clinical trials, it has become important to better molecularly define patients to distinguish between true PMD, phenocopies and guide patients to the proper therapeutic strategies. The North American Mitochondrial Disease Consortium (NAMDC) has been instrumental in centralizing patients with PMD into a unified registry and biorepository, yet 40.1% of these patients remain without a definite genetic diagnostic hindering meaningful participation in specific natural history studies, research and clinical trials. To address this gap, we propose to build a new system within the NAMDC registry where these patients are readily identified and processed for genetic analysis to identify a molecular basis of their disease and potentially discover novel genes causing PMD. This project calls for a NAMDC-wide engagement from 1) all NAMDC site investigators to keep the registry data-entry updated for existing and new participants, 2) NAMDC core personnel to establish a new built-in electronic mechanism within the NAMDC registry intake-form to flag genetically negative participants for prompt identification and evaluation at time of participant enrollment. 3) primary site at Columbia University Medical Center to perform appropriate genomic approaches for molecularly undefined cases and 4) NAMDC sites with expertise in analyzing molecular data and for potential follow up functional studies for new gene variants. Moreover, this project will use tools developed by the consortium in the form of the new research diagnostic criteria for PMD to help identify patients with the strongest phenotypes for PMD and thus highest yield for genetic findings and discoveries. The long-term goal of this project is to have 100% molecular coverage for all NAMDC registry participants. This will improve patients? assignment in specific cohorts based on their genotype, which in turn will provide more accurate natural history studies, help develop targeted outcome measures based on objective patient?s characteristics and select the most appropriate participants for PMD clinical trials. . OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page